This project will investigate nitric oxide (NO) participation in the regulation of uterine relaxation and of uterine blood vessel dilation during pregnancy in primates. These studies will pursue our preliminary evidence that the NO/NO synthase (NOS) system is a major relaxant factor that allows the progesterone-dominated uterus to remain quiescent and well-perfused during pregnancy. Proposed experiments focus on smooth muscle cells (SMC) of both the myometrium and spiral arteries as single cells or in vitro strips from rhesus macaques. Experiments will be carried out to better define the cellular basis of myometrial relaxation and spiral arterial vasodilation by NO. Modulation of myometrial contractions by NO will be studied during different stages of pregnancy, and during defined states of influence by estrogens and progestins. Direct manipulation of NO production will be carried out using methyl esters of L-arginine, which are known to block the NO synthetic pathway. Alterations induced by L-arginine methyl ester treatments will allow determination of how changes in NO production affect the SMC during pregnancy. NO modulation of dilation of spiral arteries which supply the decidua, and thus provide for respiratory and nutrient exchange with the fetus, will be studied. Changes in NO-induced vasorelaxation occurring during later stages of pregnancy, as altered by steroidal or nitroxidogenic treatment, will be explored. The state of excitability of both spiral arteries and the myometrium will also be probed by stimulation with potassium chloride and prostaglandins, with and without block of NO production. These studies will show how NO influences excitability of the myometrium and dilation of essential arteries that provide placental blood supply during pregnancy. New fundamental information will provide an improved understanding of local modulation of contractile activity and blood supply to the uterus during pregnancy, and perhaps add Insight to problems leading to pre-term labor.